Natural killer (NK) cells are large granular lymphocytes capable of killing tumor cells and certain virally infected cells in a non-MHC restricted manner. These properties afford NK cells the potential to play a role not only in host defense against viral pathogens, but in immune surveillance against the establishment of primary tumors. Indeed, in vitro expansion of NK cells (in this setting referred to as lymphokine activated killer, or LAK cells) has been exploited clinically as a therapy for certain kinds of cancer. The molecular interactions responsible for target cell recognition by NK cells are poorly understood. By definition, NK cells do not express cell surface CD3, or any known target recognition structure analogous to the T cell antigen receptor heterodimers (alphabeta or gammadelta). We have recently shown that human NK cells do, however, express the zeta chain of the T cell receptor (TCR) complex. In NK cells, zeta is found in equal amounts as a disulfide linked homodimer, and as a disulfide liked heterodimer composed of zeta and a novel 12 kd molecule. In contrast to T cells, which express zeta in association with CD3:TCR, NK cells express zeta in association with two clonally variable surface molecules designated p60-70 and p80-90. We have been able to show that one of these zeta- associated molecules (p60-70) is CD16, an Fc receptor employed by NK cells to effect antibody dependent cell mediated cytolysis. It remains to be determined whether the zeta NK receptor complex (comprised of zeta:zeta, zeta:p12, CD16, and p80-90) is also responsible for antibody independent, non-MHC restricted killing of tumor cells. The overall aim of this project is to determine the role of the zeta NK complex in the cytolytic effector function mediated by human NK cells. The specific aims are: i) To determine whether the zeta subunit is phosphorylated in response to NK cell activation by susceptible target cells, ii) To determine whether CD2 is included in the zeta NK complex, iii) To determine the structure of p12 and p80-90, and iv) To determine whether p80-90 is involved in NK cell activation. These aims will be accomplished by determining the role of each subunit of the zeta NK complex in antibody dependent and antibody independent killing mediated by NK cells. We will also determine whether the subunit composition of the zeta NK complex differs on individual NK cells, and whether these differences affect NK cell killing. Finally, we will use polyclonal and monoclonal antibodies reactive with p12 and p80-90 to determine the structure and function of these newly identified zeta NK subunits.